Study Shows Protein-Making Machinery Can Switch Gears with a Small Structural Change

By Eric Sauter and Mika Ono

For the past several years, Min Guo, an assistant professor
at The Scripps Research Institute (TSRI), has focused on the intricate actions
of an ancient family of catalytic enzymes that play a key role in translation,
the process of producing proteins.

These complex enzymes are a group of fundamental molecules that
make building blocks for protein production. Present in every cell, these
enzymes—known as aminoacyl-transfer RNA synthetases (tRNA synthetases)—select
the proper amino acids and assign them to transfer RNAs to make a protein in
the ribosome. As an essential step of determining the genetic code, tRNA
synthetases have been around for billions of years.

However, this essential part of the protein-making machine did
not stop evolving. Now, in a new study published online ahead of print on
November 15, 2012, by the journal Molecular
Cell, Guo, Ehud Razin of The Institute for Medical Research Israel-Canada, and a large team of international
scientists have shown that this enzyme can actually also work in another
fundamental process in humans. In this case, the enzyme activates a process that
creates a copy of RNA from DNA—transcription, which is the first step leading
to gene expression. All this takes is a single chemical alteration (phosphorylation)
at a specific site on the enzyme, which then triggers a cascade of structure changes,
freeing the enzyme from translation to another role—that is, regulating transcription.

“If you think about the structural changes that occur in the synthetase
we looked at in the study, it’s very much like the movie Transformers,” Guo said. “It’s a machine that changes structure and
turns into another machine that can accomplish a completely different task—like
from a car to a giant robot. This is the first time anyone has been able to
show how you can change the function of this enzyme from a mechanistic perspective,
to know exactly how that works.”

This newly discovered ability has large implications for our
understanding of immune response, including allergies and cancer, Guo said.

He notes the unusual transformation of tRNA synthetases was
initially discovered in mast cells, which are the body’s first line of defense
against pathogens such as bacteria and viruses. To recognize pathogens and
other signs of infection, mast cells are dispersed throughout most tissues, but
are crucially located at the body’s interfaces with the environment, such as
the skin and mucosae. Activation of mast cells is a key step in initiating
allergies, in which activated mast cells secrete preformed mediators, such as
histamine, and synthesize new mediators that augment the allergic response. It
turns out that mast cells mobilize the tRNA synthetases to participate in
transcriptional regulation and carry along this entire signal cascade within
minutes.

“This shows how a housekeeping machine can be reshaped for a regulatory
response,” Guo said, “something that is only now starting to get noticed.”

Recent research has also shown that the transformed
synthetase in the new study also increases metastasis in breast cancer cells.

“By designing a way to prevent this synthetase
transformation, you could potentially limit metastasis,” Guo said. “But you
have to know the mechanism before you can design something to alter it. This
new study gives us a basic framework that shows how this transformation works.”

The first authors of the study, “Structural Switch
of Lysyl-tRNA Synthetase between Translation and Transcription,” are Yifat
Ofir-Birin of The Institute for Medical Research Israel-Canada and Pengfei Fang
of TSRI. In addition to Guo, Razin, Ofir-Birin and Fang, other authors include
Steven P. Bennett, Jing Wang, Ryan Shapiro, Jorge Pozo, Paul Schimmel and
Xiang-Lei Yang of TSRI (Sharpiro and Schimmel are also affilitated with the
Skaggs Institute for Chemical Biology at TSRI); Inbal Rachmin, Jing Song and Arie
Dagan of The Institute for Medical Research Israel-Canada; Hui-Min Zhang and
Alan G. Marshall of Florida State University; Sunghoon Kim of Seoul National
University; and Hovav Nechushtan of the Hadassah Medical Center, Israel.

“This study required teamwork,
as it spanned the
boundaries of different biological fields, including cell biology, structural
biology, immunity and cancer,” Guo said. “This and future work is made possible
by the close collaborations among scientists around the world.”

The study was supported by the National Institutes
of Health (grant numbers GM088278; GM23562; GM78359; and GM100136); National
Science Foundation Division of Materials Research; the National Foundation for
Cancer Research; the Global Frontier Project and the Ministry of Education,
Science and Technology, Korea; the Israel Science Foundation; the United States
Binational Science Foundation; the National Research Foundation of Singapore;
the German-Israel Foundation for Scientific Research and Development; the
Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum;
the Israel Ministry of Science and Technology; the State of Florida; and the U.
S. Department of Energy.